Compositions and methods for treating or preventing diseases associated with oxidative stress

ABSTRACT

Methods and compositions for treating various indications by lessening oxidative stress in a patient are provided. A pharmaceutical composition comprises between about  0.001 % to about  10.0 %, or more specifically between about  0.015 % to about  5 %, sodium iodide or catalase by weight. The iodine ion or the catalase dissociates hydrogen peroxide into water and molecular oxygen to interrupt biological events that result in negative side effects. The pharmaceutical composition further comprises in some cases a reducing agent or various carrier materials. The pharmaceutical composition is in some cases formulated for a variety of delivery methods.

CROSS-REFERENCE

This application is a divisional of Application Ser. No. 14/387,803filed on Sep. 24, 2014, which is a 371 of PCT/US2013/034467 filed onMar. 28, 2013, which claims priority to U.S. Provisional Application No.61/617,501, filed Mar. 29, 2012, and the contents of each of theforegoing applications are incorporated herein by reference in theirentirety.

BACKGROUND

Collagen cross-linking is a parasurgical treatment for multipleophthalmic disorders. In some cases, collagen cross-linking may also becombined with other treatments to improve corneal strength or opticalrefraction. Treatment methods include mini asymmetric radial keratotomy,corneal ring segment inserts, or topography-guided laser. Correctivelenses are normally required after these treatments, but with smaller,more normalized prescriptions. Increased corneal symmetry allows formore comfortable contact lens wear, often of daily disposable lenses.Collagen crosslinking limits deterioration of vision, increases unaidedand uncorrected vision, and may reduce the need for cornealtransplantation.

SUMMARY

Disclosed herein, in certain embodiments, is a pharmaceuticalcomposition for treating oxidative stress in an individual in needthereof, comprising (a) 0.001% to 10.0% sodium iodine or catalase byweight, and (b) a pharmaceutically-acceptable excipient. In someembodiments, the pharmaceutical composition comprises about 0.015% toabout 5% sodium iodine or catalase by weight. In some embodiments, thepharmaceutical composition comprises about 0.001%, about 0.01%, about0.1%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about7%, about 8%, about 9%, or about 10% sodium iodide or catalase byweight. In some embodiments, the composition has a basic pH. In someembodiments, the basic pH is between 7 and 8.4. In some embodiments, thepharmaceutical composition further comprises a reducing agent. In someembodiments, the reducing agent is thiosulfate, vitamin C, or sodiumbisulfate. In some embodiments, the pharmaceutically-acceptableexcipient is a thickener, an oil phase, a surfactant, a preservative, ora pH adjusting agent. In some embodiments, the pharmaceuticalcomposition is a solution, emulsion, cream, ointment, lotion, gel,powder, solid, tincture, paste, vapor, tape, or lotion.

Disclosed herein, in certain embodiments, is a method of treating adisease, disorder or condition characterized by unwanted or excessiveoxidative stress in an individual in need thereof, comprisingadministering to the individual a pharmaceutical composition comprisingabout 0.001% to about 10.0% sodium iodine or catalase by weight. In someembodiments, the pharmaceutical composition comprises about 0.015% toabout 5% sodium iodine or catalase by weight. In some embodiments, thepharmaceutical composition comprises about 0.001%, about 0.01%, about0.1%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about7%, about 8%, about 9%, or about 10% sodium iodide or catalase byweight. In some embodiments, the composition has a basic pH. In someembodiments, the basic pH is between 7 and 8.4. In some embodiments, thepharmaceutical composition further comprises a reducing agent. In someembodiments, the reducing agent comprises thiosulfate, vitamin C, orsodium bisulfate.

In some embodiments, the disease, disorder or condition is ectasia. Insome embodiments, the disease, disorder or condition is Glaucoma; DryEyes; Degenerative Retinal Damage (ARMD); Cataractogenesis; Retinopathyof Prematurity (ROP); Ocular Uveitis; or Cataracts. In some embodiments,the disease, disorder or condition is Burns, Dermatitis; Psoriasis;Vitiligo, Androgenic Alopecia; or Onset of Gray Hair.

In some embodiments, the disease, disorder or condition is arthritis. Insome embodiments, the disease, disorder or condition is Keshan Disease;Myocardial Infarction; Atherosclerosis; Arterial Sclerosis. In someembodiments, the disease, disorder or condition is Asthma; AcuteRespiratory Distress Syndrome (ARDS); Hyperoxia and Pulmonary Edema. Insome embodiments, the disease, disorder or condition is InflammatoryBowel Disease (IBD); Crohn's Disease; Ischemic Bowel Disease; Cancer;Inflammatory Immune Response; Diabetes; Injury Ischemia Reflow Injury;Vasospasm; Hemolytic Anemia; Progeria and Progressive SystemicSclerosis. In some embodiments, the disease, disorder or condition isHepatic Cirrhosis; Renal Graft; Glomerulonephritis and Endotoxin LiverInjury. In some embodiments, the disease, disorder or condition isParkinson's Disease; Alzheimer's Disease; Schizophrenia; Cerebral Edema;Cerebral Infarction; Epilepsy; Bipolar Disorder. In some embodiments,the disease, disorder or condition is Wrinkling; Baldness; Presbyopia;Cataracts; Hearing loss; Hypertension; Memory loss.

Disclosed herein, in certain embodiments, is a method of healing awound, comprising contacting the wound with a pharmaceutical compositioncomprising about 0.001% to about 10.0% sodium iodine or catalase byweight. In some embodiments, the pharmaceutical composition comprisesbetween about 0.015% to about 5% sodium iodine or catalase by weight. Insome embodiments, the pharmaceutical composition comprises about 0.001%,about 0.01%, about 0.1%, about 1%, about 2%, about 3%, about 4%, about5%, about 6%, about 7%, about 8%, about 9%, or about 10% sodium iodideor catalase by weight. In some embodiments, the composition has a basicpH. In some embodiments, the basic pH is between 7 and 8.4. In someembodiments, the pharmaceutical composition further comprises a reducingagent. In some embodiments, the reducing agent comprises thiosulfate,vitamin C, or sodium bisulfate. In some embodiments, the wound isassociated with refractive corneal surgery, thermokeratoplastytreatment, lens-based refractive surgery, retinal surgery, scleralsurgery, retinal or glaucoma laser surgery, cataract and eye lidsurgery, heart surgery. In some embodiments, the corneal surgery is PRK,LASIK, Intacs, lamellar corneal procedures, CK, or any combinationsthereof. In some embodiments, the heart surgery is angioplasty.

Disclosed herein, in certain embodiments, is a method of reducing orpreventing oxidative stress in a tissue undergoing photochemicalcrosslinking, comprising contacting the tissue with a pharmaceuticalcomposition comprising between about 0.001% to about 10.0% sodium iodineor catalase by weight. In some embodiments, the pharmaceuticalcomposition comprises between about 0.015% to about 5% sodium iodine orcatalase by weight. In some embodiments, the pharmaceutical compositioncomprises about 0.001%, about 0.01%, about 0.1%, about 1%, about 2%,about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, orabout 10% sodium iodide or catalase by weight. In some embodiments, thecomposition has a basic pH. In some embodiments, the basic pH is between7 and 8.4. In some embodiments, the pharmaceutical composition furthercomprises a reducing agent. In some embodiments, the reducing agentcomprises thiosulfate, vitamin C, or sodium bisulfate.

Disclosed herein, in certain embodiments, are compositions for reducingoxidative stress, comprising iodide ion and apharmaceutically-acceptable excipient. In some embodiments, thecomposition is safe. In some embodiments, the composition lessensoxidative stress in vivo. In some embodiments, the composition comprisessodium iodide (NaI). In some embodiments, the composition comprisesbetween about 0.001% to about 10.0% sodium iodide by weight. In specificembodiments, the composition comprises between about 0.015% to about 5%sodium iodide by weight. In some embodiments, the iodide ion is kept inthe ionized form by maintaining the composition at a basic pH. In somespecific embodiments the pH of the composition is between about 7.0 andabout 8.4.Included in the embodiments described herein are allcombinations and subcombinations of ranges and specific integersencompassed therein.

Other features and advantages of the present disclosure will become morereadily apparent to those of ordinary skill in the art after reviewingthe following detailed description and accompanying drawings.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

After reading this description it will become apparent to one skilled inthe art how to implement the compositions and methods of the presentdisclosure in various alternative embodiments and alternativeapplications. However, although various embodiments of the presentdisclosure will be described herein, it is understood that theseembodiments are presented by way of example only, and not limiting. Assuch, this detailed description of various alternative embodimentsshould not be construed to limit the scope or breadth of the presentdisclosure as set forth in the appended claims.

Cells obtain energy from the oxidation of a variety of organicmolecules, and oxygen is the primary oxidant in the biochemicalreactions that perform this function. Oxidative stress represents animbalance between the production and manifestation of reactive oxygenspecies and a biological system's ability to readily detoxify thereactive intermediates or to repair the resulting damage.

In humans, oxidative stress contributes to diseases ranging fromAlzheimer's, heart disease and stroke to macular degeneration (theleading cause of adult blindness), dry eye, glaucoma and cancer.However, increased oxidative stress also causes an adaptive reactionwhich produces increased stress resistance and a long-term reduction ofoxidative stress (in a process names mitohormesis). Mitohormesis isassociated with the anti-aging effects of glucose restriction andphysical exercise.

The compositions of the present disclosure comprise catalase and/oriodide ion, decrease oxidative stress in vivo and exhibit a beneficialor salutary effect on many diseases and health maintenance.

The anti-oxidative compositions described herein are capable oftreating, reversing or partially reversing, or preventing diseasesassociated with oxidative stress due to active oxygen species, freeradicals, or the like, in vivo, thereby preventing the occurrence orworsening of a disease or condition.

Exemplary Terms

As used herein, the terms “comprising,” “including,” and “such as” areused in their open, non-limiting sense.

The term “about” is used synonymously with the term “approximately.”Illustratively, the use of the term “about” indicates that valuesslightly outside the cited values, i.e., plus or minus 0.1% to 10%,which are also effective and safe.

“Antioxidants” include, e.g., butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA), sodium ascorbate, and tocopherol.

“Binders” impart cohesive qualities and include, e.g., alginic acid andsalts thereof; cellulose derivatives such as carboxymethylcellulose,methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®),ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g.,Avicel®); microcrystalline dextrose; amylose; magnesium aluminumsilicate; polysaccharide acids; bentonites; gelatin;polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone;starch; pregelatinized starch; tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum suchas acacia, tragacanth, ghatti gum, mucilage of isapol husks,polyvinylpyrrolidone (e.g., Polyvidone®, CL, Kollidon® CL, Polyplasdone®XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodiumalginate, and the like.

“Bioavailability” refers to the extent to which an active moiety, e.g.,drug, prodrug, or metabolite, is absorbed into the general circulationand becomes available at the site of drug action in the body. Thus, acompound administered through IV is 100% bioavailable. “Oralbioavailability” refers to the extent to with the compound is absorbedinto the general circulation and becomes available at the site of thedrug action in the body when a compound is taken orally.

“Carrier materials” include any commonly used excipients inpharmaceutics and should be selected on the basis of compatibility withthe active ingredient and the release profile properties of the desireddosage form. Exemplary carrier materials include, e.g., binders,suspending agents, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, wetting agents, diluents, and thelike. See, e.g., Remington: The Science and Practice of Pharmacy,Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, JohnE., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott William &Wilkins 1999).

“Oxidative stress” refers to the condition characterized by an excess ofoxidants and/or a decrease in antioxidant levels. Cellular oxidantsinclude, but are not limited to, one or more of: radicals of oxygen(superoxide anion, hydroxyl radical, and/or peroxy radicals); reactivenon-radical oxygen species such as, for example, hydrogen peroxide andsinglet oxygen; carbon radicals; nitrogen radicals; and sulfur radicals.The condition of oxidative stress results in, for example, cellulardamage, inflammation, impaired performance of cells and/or cell death.

“Prevent” or “prevention” means no disorder or disease development ifnone had occurred, or no further disorder or disease development ifthere had already been development. Also considered is the ability ofone to prevent or reduce some or all of the symptoms associated with thedisorder or disease.

“Surfactants” include compounds such as sodium lauryl sulfate, sorbitanmonooleate, polyoxyethylene sorbitan monooleate, polysorbates,polaxomers, bile salts, glyceryl monostearate, copolymers of ethyleneoxide and propylene oxide, e.g., Pluronic® (BASF); and the like.

A “therapeutically effective amount” or “effective amount” is thatamount of a compound, material, composition, and/or dosage form asdescribed herein that is in at least some cases effective to achieve aparticular biological result. Such results in at least some casesinclude, but are not limited to, reduction and/or prevention ofoxidative stress. Such effective activity is achieved in at least somecases, for example, by causing the ingestion of compositions accordingto aspects of the present disclosure. The term “therapeuticallyeffective amount” includes, for example, a prophylactically effectiveamount. An “effective amount” is an amount effective to achieve adesired pharmacologic effect or therapeutic improvement without undueadverse side effects. The effective amount of a pharmaceutical agentwill be selected by those skilled in the art depending on the particularpatient and the disease level. It is understood that “an effectiveamount” or “a therapeutically effective amount” varies in at least somecases from subject to subject, due to variation in metabolism oftherapeutic agents, age, weight, general condition of the subject, thecondition being treated, the severity of the condition being treated,and the judgment of the prescribing physician.

“Treat” or “treatment” includes preventing a disorder or disease fromoccurring in a subject which may be predisposed to the disorder ordisease, but has not yet been diagnosed as having the disorder ordisease; inhibiting the disorder or disease, e.g., arresting thedevelopment of the disorder or disease, relieving the disorder ordisease, causing regression (or partial regression) of the disorder ordisease, relieving a condition caused by the disease or disorder,stopping the symptoms of the disease or disorder, or reversing orpartially reversing certain diseases and/or conditions. Thus, as usedherein, the term “treat” is used synonymously with the term “prevent.”

Oxidative Stress Cycle

Oxidative stress processes often have a self-regenerating nature. Forexample, oxidative stress leads to further oxidative stress and thecycle reinforces itself. By way of example only, moderate H₂O₂ or OH⁻disrupts the mitochondria of cells causing an increase of superoxideanion production. Disruption of mitochondria leads to increased hydrogenperoxide production and the effect becomes exponentiallyself-regenerating. This often results in a severe disorder. Disruptionof an oxidative stress cycle allows natural mechanisms to address thesource of the initial oxidative stress.

In certain instances, increased or undesired peroxide levels in a tissue(for example, ocular tissue) results from the inactivation (in areversible reaction) of endogenous catalase by nitric oxide. Catalaseactivity is affected by the presence of nitric oxide which binds to theactive center of catalase. When the nitric oxide molecule is present thecatalase is unable to attach itself to a peroxide molecule. As thepartial pressure of nitric oxide gas in the tissue drops, the nitricoxide dissociates from the catalase and the catalase becomes activeagain. Thus nitric oxide is a reversible inhibitor of catalase.

Inactivation of catalase results in the build-up of peroxide whichresults in damage to a tissue and an inflammatory response. As theinflammatory response increases, more nitric oxide is produced renderingmore catalase inactive and increasing the concentration of peroxide.Because nitric oxide prevents the catalase from working, addingadditional catalase often does not fully inhibit or sufficiently reduceperoxide build-up. In some embodiments, iodide ion inhibits the build-upof peroxide because the iodide ion is not subject to inactivation bynitric oxide.

There are a number of agents that inactivate catalase, and result in thebuild-up of the oxidative cycle and cell death. For example, manychemotherapeutic agents are designed to activate or increase theoxidative cycle. Calcitriol, a catalase inhibitor, is used to killcancer cells by peroxide build up.

Pharmaceutical Compositions

Disclosed herein, in certain embodiments, are compositions for reducingoxidative stress, comprising iodide ion and apharmaceutically-acceptable excipient. In some embodiments, thecomposition comprises sodium iodide (NaI), catalase or a combinationthereof. In some embodiments, the composition comprises between about0.001% to about 10.0% sodium iodide by weight. In specific embodiments,the composition comprises between about 0.015% to about 5% sodium iodideby weight. In some embodiments, the iodide ion is kept in the ionizedform by maintaining the composition at a basic pH. In some specificembodiments the pH of the composition is between about 7.0 and about8.4. In some embodiments, the composition is safe. In some embodiments,the composition lessens oxidative stress in vivo. Included in theembodiments described herein are all combinations and subcombinations ofranges and specific integers encompassed therein.

In some embodiments, the compositions disclosed herein react as follows:

H₂O₂(aq)+I⁻(aq)→IO⁻(aq)+H₂O(l)   Step 1

H₂O₂(aq)+IO⁻(aq)→I⁻(aq)+H₂O(l)+O₂(g)   Step 2

These equations describe the reaction that occurs between iodide ion andhydrogen peroxide in basic solutions (pH of 7.0 or higher). The netresult of the above equations is:

2H₂O₂+I⁻→2H₂O+O₂+I⁻

This illustrates the iodide ion is just a catalyst and is unchangedduring the reaction. Iodide ion is a catalyst to break hydrogen peroxideinto water and oxygen in non-acidic solutions, but in acidic solutionsthe following reaction occurs:

H₂O₂(aq)+3I⁻(aq)+2H⁺→I₂(aq)+2H₂O+I⁻

In oxidizing acid solutions the reaction of iodide ion and peroxide(referred to in the chemical literature as the Iodide Clock Reaction)will precipitate elemental iodide out of solution.

In some embodiments of the pharmaceutical compositions described herein,a reducing agent is included. Non-limiting examples of reducing agentsinclude sodium thiosulfate, vitamin C or sodium bisulfate.

Below is an example of the reaction of iodide with the thiosulfate:

I₂(aq)+2S₂O₃ ²⁻(aq)→S₄O₆ ²⁻(aq)+2I⁻(aq)

An advantage of an iodide ion as a peroxide reducing agent in inflamedtissue is that it is not persistent in the tissue. Once the peroxidecycle has been broken and inflammation subsides the NO pressure dropsand the native catalase keeps the peroxide at a normal basal level. Insome embodiments, other enzymes also begin to work once the peroxidelevels drop.

The compositions described herein are administered and dosed inaccordance with good medical practice, taking into account the clinicalcondition of the individual patient, the site and method ofadministration, scheduling of administration, and other factors known tomedical practitioners. In human therapy, it is important in many casesto provide a dosage form that delivers the required therapeutic amountof the drug in vivo, and renders the drug bioavailable in a timelymanner.

Treatment dosages generally are titrated to optimize safety andefficacy. Typically, dosage-effect relationships from in vitro and/or invivo tests initially provide useful guidance on the proper doses forsubject administration. Studies in animal models generally are used forguidance regarding effective dosages for treatment of the conditions,disorders or diseases in accordance with the present disclosure. Interms of treatment protocols, it should be appreciated that the dosageto be administered will depend on several factors, including theparticular agent that is administered, the route chosen foradministration, the age of the subject, and the condition of theparticular subject.

In some embodiments, unit dosage forms of the pharmaceuticalcompositions disclosed herein comprise between about 0.001% to 10.0%sodium iodide by weight. In specific embodiments, the pharmaceuticalcompositions comprise between about 0.015% to about 5% sodium iodide byweight. In some embodiments, the pharmaceutical compositions compriseabout 0.001%, about 0.01%, about 0.1%, about 1%, about 2%, about 3%,about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%sodium iodide by weight. Included in these embodiments are allcombinations and subcombinations of ranges and specific integersencompassed therein.

Generally speaking, one will desire a pharmaceutical composition thatprovides an amount of an iodide ion that is effective to achieve thetherapeutic effect desired when administered to a subject. Determinationof these parameters is well within the skill of the art. Theseconsiderations are well known in the art and are described in standardtextbooks.

Photochemical Crosslinking Compositions

Described herein are compositions for photochemical crosslinkingcomprising (1) riboflavin, and (2) an iodide ion and/or catalase. Insome embodiments, the compositions are saturated with oxygen. In someembodiments, the compositions comprise a higher oxygen content thanexisting compositions. In some embodiments, the compositions furthercomprise artificial tear solutions, for example to keep the eye hydratedduring the procedure or to reoxygenate the eye during the procedure. Insome embodiments, the compositions further comprise a high lipidsolution (or other ingredient) for reoxygenation. In some embodiments,the iodide ion and/or catalase enzyme serve to decompose hydrogenperoxide into water and molecular oxygen.

Iodide ions are small and mobile and exhibit little difficulty gettinginto the corneal stroma where the crosslinking takes place. Iodide ionsalso exhibit rapid diffusion and lack of post-procedural persistence.Catalase is a large enzyme and as a result it is difficult for thecatalase to penetrate into the corneal stroma where the crosslinkingtakes place. When a catalase enzyme is used, steps must be taken earlyin the crosslinking procedure to disrupt the barrier functions of thecorneal epithelium for riboflavin infusion. This reduced barrierfunction also allows easy introduction of the iodide ion. Non-limitingexamples of epithelial barrier disruption include mechanical treatmentsand the use of chemicals such as benzylalkonium chloride.

Catalase enzyme is excellent for the decomposition of the peroxide inthe following ways; it's naturally found in tissue and cells, it's notpH sensitive, and it doesn't quench the photochemical reaction betweenriboflavin and UV/blue light. Catalase enzyme works well inphotochemical crosslinking compositions disclosed herein to protect theviability of the riboflavin against oxidation during storage andtransport, and work well on the corneal epithelium to protect theepithelium from peroxide damage.

Topical Formulations

In some embodiments of the disclosure described herein, thepharmaceutical composition is a topical formulation comprising an iodideion and at least one carrier material. Non-limiting examples of carriermaterials useful in the topical formulations disclosed herein are:thickeners, including gums, celluloses, acrylic acids, colloidal solids,hydrogels, and thermoreversible polymers; oil phases; surfactants,including non-ionic, anionic, and cationic; solvents, including polarand non-polar; preservatives, including antimicrobial, antioxidants andchelating agents; and pH adjustors, such as diethanolamine, lactic acid,monoethanolamine, triethanolamine, sodium hydroxide and sodiumphosphate.

In various embodiments, the topical formulation is formulated for directapplication to a body surface including but not limited to the skin ormucous membranes such as the vagina, anus, throat, eyes and ears. Insome embodiments, the topical formulation is epicutaneous, i.e. directlyapplied to the skin. In various embodiments, the topical formulation isin the form of a cream, ointment, shake lotion, gel, powder, solid,transdermal patch, tincture, paste, vapor, tape, sponge or lotion.

Intravenous Formulations

In some embodiments of the disclosure described herein, thepharmaceutical composition is an intravenous formulation comprising aniodide ion and at least one carrier material. Non-limiting examples ofcarrier materials useful in the intravenous formulations disclosedherein are surfactants, including non-ionic, anionic, and cationic;solvents, including polar and non-polar; preservatives, includingantimicrobial, antioxidants and chelating agents; and pH adjustors, suchas diethanolamine, lactic acid, monoethanolamine, triethanolamine,sodium hydroxide and sodium phosphate.

Iontophoresis Delivery

In some embodiments of the disclosure described herein, thepharmaceutical composition is delivered through iontophoresis. In theseembodiments, two electrodes are placed in contact with tissue, one ofthe electrodes being a pad of absorbent material soaked with a solutioncontaining the iodide ion, and a voltage is applied between theelectrodes to deliver the ion to the subject.

Sustained Release Formulations

In some embodiments of the disclosure described herein, thepharmaceutical composition is a sustained release formulation comprisingan iodide ion and at least one carrier material. Non-limiting examplesof carrier materials useful in the sustained release formulationsdisclosed herein are: enteric coatings, thickeners, including gums,celluloses, acrylic acids, colloidal solids, hydrogels, andthermoreversible polymers; oil phases; surfactants, including non-ionic,anionic, and cationic; solvents, including polar and non-polar;preservatives, including antimicrobial, antioxidants and chelatingagents; and pH adjustors, such as diethanolamine, lactic acid,monoethanolamine, triethanolamine, sodium hydroxide and sodiumphosphate.

In various embodiments, the sustained release formulation is anophthalmic formulation, a parenteral formulation, a pellet formulation,or a transdermal formulation.

In some embodiments, the sustained release ophthalmic formulationcomprises a water-based gel, a suspension, an ointment, an ocularinsert, or small colloidal carrier particles (such as liposomes,microspheres, microcapsules, nanoparticles, or nanocapsules). In someembodiments, the sustained release parenteral formulation comprises anoily vehicle, aqueous suspension, emulsion, microsphere, or animplantable drug delivery system. In some embodiments, the sustainedrelease transdermal formulation comprises an iodide ion in an adhesivelayer, a polymeric matrix layer, a reservoir layer or a peripheraladhesive layer.

Implants

In some embodiments of the disclosure described herein, thepharmaceutical composition is delivered through an implant comprising aniodide ion and at least one carrier material. In various embodiments,the implant is composed of a number of capsules. In some embodiments theimplant is biodegradable.

Methods of Treatment

Disclosed herein, in certain embodiments, are methods of reducing orpreventing oxidative stress processes in an individual in need thereof,comprising administering to the individual a composition comprisingsodium iodide, catalase, or combinations thereof. In some embodiments,the method comprises administering a composition comprising betweenabout 0.001% to about 10.0% sodium iodide by weight. In someembodiments, the method comprises administering a composition comprisingbetween about 0.015% to about 5% sodium iodide by weight. In someembodiments, the composition has a basic pH. In some embodiments, the pHof the composition is between about 7.0 and about 8.4.

As discussed above, increased or undesired peroxide levels in a tissue(for example, ocular tissue) results from the inactivation (in areversible reaction) of endogenous catalase by nitric oxide. Theinactivation of catalase is associated with the destruction of nervecells (glaucoma), retinal macular cells (AMD), lacrimal and epithelialcells (dry eye) and lens cells (cataract). In some embodiments, themethods described herein replace or supplement the function ofinactivated catalase. In some embodiments, supplementation orreplacement of catalase activity reduces or prevents oxidative stressprocesses.

In certain instances, peroxide inhibits or reduces the activity ofenzymes needed for the proper functioning of a cell. In certaininstances, these effects are reversible when the peroxide levels arelowered. In some embodiments, the methods described herein reverse theeffects of undesired peroxide.

Photochemical Crosslinking

Disclosed herein, in certain embodiments, are methods of reducing orpreventing oxidative stress processes in a tissue undergoingphotochemical crosslinking, comprising administering to the tissue acomposition comprising sodium iodide, catalase, or combinations thereof.In some embodiments, the method comprises administering a compositioncomprising between about 0.001% to about 10.0% sodium iodide by weight.In some embodiments, the method comprises administering a compositioncomprising between about 0.015% to about 5% sodium iodide by weight. Insome embodiments, the composition has a basic pH. In some embodiments,the pH of the composition is between about 7.0 and about 8.4. In someembodiments, the tissue is a cornea. In some embodiments, the tissue issclera.

In some embodiments, photochemical crosslinking further comprisesremoving the epithelium of the cornea and/or sclera, pretreating thecornea and/or sclera with chemicals (or utilizing other means toincrease permeability of the surface of the cornea) before the tissue isirradiated. In some embodiments, pretreatment allows riboflavin and theiodide ions to readily penetrate into the stroma for crosslinking.

Diseases

Further disclosed herein, in certain embodiments, are methods oftreating diseases, disorders or conditions associated with oxidativestress processes in an individual in need thereof, comprisingadministering to the individual a composition comprising sodium iodide,catalase, or combinations thereof. In some embodiments, the methodcomprises administering a composition comprising between about 0.001% toabout 10.0% sodium iodide by weight. In some embodiments, the methodcomprises administering a composition comprising between about 0.015% toabout 5% sodium iodide by weight. In some embodiments, the compositionhas a basic pH. In some embodiments, the pH of the composition isbetween about 7.0 and about 8.4.

Non-limiting examples of diseases and disorders for which theiodide-based solutions described here are useful include glaucoma,macular degeneration (wet and dry), cataract formation, keratoconus,cystoid macular edema, dry eye syndrome and quite a few more. Ingeneral, these conditions are described as oxidative ophthalmicdisorders and the purpose of the pharmaceutical compositions describedherein is to provide therapeutic relief to patients suffering fromoxidative disorders by removal of peroxides. These applications are notspecific to a particular anatomical part of the eye and in someembodiments are used to treat any ocular tissues that are exhibiting apathogenesis of oxidative stress including but not limited toinflammation. In some embodiments, some of these conditions lead toirreversible vision loss and there are no current drugs or treatmentsavailable for some of these conditions.

In some embodiments the pharmaceutical compositions described herein isused to treat macular, retinal or scleral disorders. The compositionsdisclosed herein are introduced into an eye by any suitable methods. Inthese embodiments, the iodide ion is introduced by injection of iodideion into the vitreous humor, using trans-scleral methods or implants oftime released capsules or impregnated depot devices that slowly dissolvethe iodide ion into the different chambers/parts of the eye.

In yet other embodiments, the pharmaceutical compositions describedherein are used to treat other organ disorders, including the lungs,cardiovascular system and the brain. Amyloid beta formed in braintissues inactivates catalase and the resulting hydrogen peroxideproduction is associated with Alzheimer's disease. Pharmaceuticalcompositions that allow an iodide ion to pass the blood-brain barrierare provided herein and are used in some embodiments to treatneurological disorders associated with oxidative stress.

Ectasia

Further disclosed herein, in certain embodiments, are methods oftreating ectasia in a subject in need thereof, comprising administeringto the subject a composition comprising sodium iodide, catalase, orcombinations thereof. In some embodiments, the method comprisesadministering a composition comprising between about 0.001% to about10.0% sodium iodide by weight. In some embodiments, the method comprisesadministering a composition comprising between about 0.015% to about 5%sodium iodide by weight. In some embodiments, the composition has abasic pH. In some embodiments, the pH of the composition is betweenabout 7.0 and about 8.4.

In many post-operative surgical procedures negative side effects to thecornea and/or sclera are observed due to biological reactions termed“wound healing response”. This wound healing response is the body's wayof forming protective scar tissues when injury has been done.

In the cornea and/or sclera, the wound healing response is initiated bythe surgical intervention. The primary means of orchestrating the woundhealing response is by several cytokines that are released as result ofthe injury. These cytokines often use H₂O₂ as the secondary messengermolecules for stimulating the production of the new scar tissue,promoting edema, and changing the cellular functioning.

The corneal and scleral wound healing cycles are in at least some casesinterrupted by adding an iodide ion or catalase into the eye before orshortly after the wound healing response begins. In some embodiments,iodide ion or catalase interrupts the corneal or scleral wound healingcycles. In some embodiments, dissociating H₂O₂ into water and molecularoxygen interrupts the corneal or scleral wound healing cycles. Thisinterruption breaks the cascade of biological events that results inundesired side effects.

The cornea is particularly sensitive to oxidative stress. Hydrogenperoxide reacts with ambient UV and visible light in the blue spectrumto break apart into 2 OH⁻ ions, which are the most destructive forms ofROS in the body.

The methods, compounds, and compositions described herein find use inthe treatment of conditions characterized by oxidative stress or damage.As discussed infra, oxidative damage plays a role in the pathogenesis ofmany diseases. Non-limiting examples of diseases known to be associatedwith oxidative stress and therefore useful in the present disclosure areprovided below.

Additional Ophthalmic Indications

In aspects of the disclosure, the methods and compositions describedherein are beneficial in the treatment of ophthalmic conditions/diseasesassociated with oxidative stress. These conditions/diseases include, butare not limited to Glaucoma; Reduction of Inflammation; Dry Eyes;Degenerative Retinal Damage (ARMD); Cataractogenesis (process ofcataract formation); Retinopathy of Prematurity (ROP); Ocular Uveitis;and Senile Cataracts.

Skin Indications

There are a number of skin conditions where the buildup of peroxide inthe skin is of concern. For example, vitiligo affects nearly 2% of theworld population and is one of the more difficult skin disorders totreat. It is known that vitiligo lesions contain very high levels ofhydrogen peroxide and it has been suggested that hydrogen peroxide ornitric oxide buildup is the root cause of the disorder. The use of thepharmaceutical compositions described herein provide an improved methodfor decomposing hydrogen peroxide in the skin for vitiligo and otherpigmentation disorders. In various embodiments the pharmaceuticalcomposition introduces the iodide ion to the skin by topicaladministration, injection or iontophoresis.

Other skin disorders associated with hydrogen peroxide build up in theskin are androgenic alopecia (loss of hair) and the premature onset ofgray hair. It has been demonstrated that superoxide anion and hydrogenperoxide build up is directly associated with both the onset of grayhair and androgenic alopecia. Provided herein, are compositions thattreat gray hair or hair loss through the decomposition of hydrogenperoxide. In various embodiments, these compositions introduce an iodideion to the skin by topical administration, injection, or iontophoresis.

In aspects of the disclosure, the methods and compositions describedherein are useful in reversing, preventing or reducing detrimental skinconditions associated with oxidative stress. These conditions include,but are not limited to, premature aging, burns, Dermatitis; Psoriasis;Vitiligo, Androgenic Alopecia (loss of hair) and Onset of Gray Hair.

Joint Indications

In aspects of the disclosure, the methods and compositions describedherein may be useful in reversing, treating or preventing jointconditions/diseases associated with oxidative stress. These conditionsinclude, but are not limited to, Inflammation; Rheumatoid Arthritis; andOsteoarthritis.

Wound Healing Indications

In aspects of the disclosure, the methods and compositions describedherein are useful in reversing, treating or preventing ocular woundsassociated with oxidative stress. These conditions include, but are notlimited to, pterygium, glaucoma, refractive corneal surgery such as PRK,LASIK, Intacs, lamellar corneal procedures, CK, and otherthermokeratoplasty treatments and lens based refractive surgery, scleralsurgery, retinal surgery or retinal or glaucoma laser surgery andintraocular such as cataract and eye lid surgery.

In some embodiments, the pharmaceutical composition is applied before orimmediately after refractive surgeries in order to accelerate healingprocess. In other embodiments, the pharmaceutical composition is appliedmultiple times during the healing process. For example, followingpainful procedures, like PRK in which the epithelium is not healed, thepharmaceutical composition are applied periodically (weekly, daily orhourly) early in the postoperative period. In specific embodiments, acontact lens or bandage is impregnated with the iodide ion or catalase.

Heart Indications

In aspects of the disclosure, the methods and compositions describedherein are useful in reversing, treating or preventing heartconditions/diseases associated with oxidative stress. These conditionsinclude, but are not limited to, Angioplasty; Keshan Disease (SeleniumDeficiency); Myocardial Infarction; Atherosclerosis (ASVD) and ArterialSclerosis.

Lung Indications

In aspects of the disclosure, the methods and compositions describedherein are useful in reversing, treating or preventing lungconditions/diseases associated with oxidative stress. These conditionsinclude, but are not limited to, Asthma; Acute Respiratory DistressSyndrome (ARDS); Hyperoxia and Pulmonary Edema.

Local or Systemic Indications

In aspects of the disclosure, the methods and compositions describedherein are useful in reversing, treating or preventing local andsystemic conditions/diseases associated with oxidative stress. Theseconditions include, but are not limited to, Inflammatory Bowel Disease(IBD); Crohn's Disease; Ischemic Bowel Disease; Cancer; InflammatoryImmune Response; Diabetes; Injury Ischemia Reflow Injury; Vasospasm;Hemolytic Anemia; Progeria and Progressive Systemic Sclerosis.

Kidney & Liver Indications

In aspects of the disclosure, the methods and compositions describedherein are useful in reversing, treating or preventing kidney and liverconditions/diseases associated with oxidative stress. These conditionsinclude, but are not limited to, Hepatic Cirrhosis; Renal Graft;Glomerulonephritis and Endotoxin Liver Injury.

Neurological Indications

In aspects of the disclosure, the methods and compositions describedherein are useful in reversing, treating or preventing neurologicalconditions/diseases associated with oxidative stress. These conditionsinclude, but are not limited to, Parkinson's Disease; Alzheimer'sDisease; Schizophrenia; Cerebral Edema; Cerebral Infarction (Stroke);Epilepsy; Bipolar Disorder; Trauma and Neurotoxins.

Aging-related Indications

In aspects of the disclosure, the methods and compositions describedherein are useful in reversing, treating or preventing diseases andsymptoms associated with aging. These conditions include, but are notlimited to, wrinkling, grey hair, baldness, presbyopia, cataracts,hearing loss, hypertension, and memory loss.

The above description of the disclosed embodiments is provided to enableany person skilled in the art to make or use the methods andcompositions of the present disclosure. Various modifications to theseembodiments will be readily apparent to those skilled in the art, andthe generic principles described herein can be applied to otherembodiments without departing from the spirit or scope of thedisclosure. Thus, it is to be understood that the description anddrawings presented herein represent a presently preferred embodiment ofthe disclosure and are therefore representative of the subject matterwhich is broadly contemplated by the present disclosure. It is furtherunderstood that the scope of the present disclosure fully encompassesother embodiments that may become obvious to those skilled in the artand that the scope of the present disclosure is accordingly not limited.

Examples

Corneal collagen cross-linking utilizing 0.5% riboflavin and 0.015% (1mmol) sodium iodide was performed in over 200 eyes. Post-operativecorneal haze, which results from keratocyte death due to the productionof hydrogen peroxide and other harmful reactive oxygen species, wasobserved to be minimal, as compared to historical cross-linkingprocedures performed without sodium iodide, in which significant cornealhaze has been observed to persist from 6 months to 1 year after thecross-linking procedure.

1. A method of treating a disease, disorder or condition characterizedby unwanted or excessive oxidative stress in an individual in needthereof, comprising administering to the individual a pharmaceuticalcomposition comprising between about 0.001% to about 10.0% sodium iodineor catalase by weight. 2.-7. (canceled)
 8. The method of claim 1,wherein the disease, disorder or condition is Glaucoma; Dry Eyes;Degenerative Retinal Damage (ARMD); Cataractogenesis; Retinopathy ofPrematurity (ROP); Ocular Uveitis; Presbyopia; or Cataracts.
 9. A methodfor photochemical crosslinking comprising administering a pharmaceuticalcomposition to the eye comprising (1) riboflavin, and (2) an iodide ion.10. The method of claim 9, wherein the pharmaceutical compositioncomprises between about 0.001% to about 10.0% sodium iodide by weight.11. The method of claim 9, wherein the pharmaceutical compositioncomprises between about 0.015% to about 5% sodium iodide by weight. 12.The method of claim 10, wherein the pharmaceutical composition comprisesabout 0.015% sodium iodide by weight and about 0.5% riboflavin byweight.
 13. The method of claim 9, wherein the composition has a basicpH.
 14. The method of claim 13, wherein the basic pH is between 7 and8.4.
 15. The method of claim 9, wherein the pharmaceutical compositionfurther comprises a reducing agent.
 16. The method of claim 15, whereinthe reducing agent comprises thiosulfate, vitamin C, or sodiumbisulfate.
 17. The method of claim 9, wherein the pharmaceuticalcomposition is used to treat wounds associated with refractive cornealsurgery, thermokeratoplasty treatment, lens-based refractive surgery,retinal surgery, scleral surgery, retinal or glaucoma laser surgery,cataract and eye lid surgery, PRK, LASIK, Intacs, lamellar cornealprocedures, CK, or any combinations thereof.
 18. A method of reducing orpreventing oxidative stress in a tissue undergoing photochemicalcrosslinking, comprising contacting the tissue with a pharmaceuticalcomposition comprising between about 0.001% to about 10.0% sodium iodideby weight.
 19. The method of claim 18, wherein the pharmaceuticalcomposition comprises between about 0.015% to about 5% sodium iodide byweight.
 20. The method of claim 18, wherein the composition has a basicpH between 7 and 8.4.
 21. A stable pharmaceutical composition for use incorneal collagen cross-linking, comprising (a) sodium iodide, (b)riboflavin, and (c) a pharmaceutically-acceptable excipient appropriatefor ocular administration, wherein the pharmaceutical compositionmaintains a basic pH that permits iodide ion to catalytically breakhydrogen peroxide into water and oxygen.
 22. The pharmaceuticalcomposition of claim 21, wherein the basic pH is between 7 and 8.4. 23.The pharmaceutical composition of claim 22, further comprising areducing agent.
 24. The pharmaceutical composition of claim 23, whereinthe reducing agent is thiosulfate, vitamin C, or sodium bisulfate. 25.The pharmaceutical composition of claim 21, wherein thepharmaceutically-acceptable excipient is an artificial tear solution.26. The pharmaceutical composition of claim 21, wherein thepharmaceutical composition is a solution adapted for introduction intothe eye and diffusion into the cornea for promoting photochemicalcorneal cross-linking and reducing oxidative.